A pressure sensitive adhesive is a material that adheres to a surface with slight pressure and releases from the surface with negligible transfer of the adhesive to the surface. Silicone pressure sensitive adhesives in particular have been used for transdermal drug delivery, which involves administering a drug by adhering a drug-containing device or patch to a patient's skin.
One type of transdermal patch is a polymer matrix or monolithic device in which the active agent is contained in a polymer matrix film through which the active agent diffuses to the skin. Such patches are preferred because they are relatively simpler to manufacture and more comfortable to wear compared to reservoir-type devices. Transdermal patches having a monolithic polymer film layer in which the active agent is contained are disclosed in U.S. Pat. No. 4,839,174, as well as in U.S. Pat. Nos. 4,908,213 and 4,943,435.
Fentanyl is an opioid analgesic which, in clinical settings, exerts its principle pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation, and it is indicated for the management of chronic pain in patients who require opioid analgesia for pain that is typically unmanageable by lesser means. In particular, fentanyl is used clinically for the relief of acute postoperative and chronic cancer pain.
Transdermal patches containing silicone pressure sensitive adhesive compositions are described in U.S. Pat. No. 5,232,702 (Pfister et al.), WO 00/33812 (Miranda et al.), WO 96/40085 (Mantelle et al.), and U.S. Pat. No. 5,603,947, all fully incorporated herein by reference.
U.S. Pat. No. 5,232,702 describes silicone pressure sensitive adhesives containing (i) a silicone fluid, (ii) a silicate resin, and (iii) a cohesive strengthening agent. In one embodiment, the pressure sensitive adhesive includes a high molecular weight polydimethylsiloxane as the silicone fluid. Organic solvents disclosed as suitable for dissolving the silicone fluid and the silicate resin include aromatics such as toluene and xylene; aliphatics such as heptane and hexane; chlorinated solvents such as 1,1,1-trichloroethane and trichlorotrifluoroethane; fluorocarbons such as Freon 113; aliphatic esters such as ethyl acetate; and mixtures thereof. Example D describes how transdermal adhesive matrix-type patches were prepared containing 17-beta estradiol, a skin penetration enhancer (PGML), a high silanol containing silicone pressure sensitive adhesive, and calcium stearate as the cohesive strengthening agent. Two different high silanol containing adhesives were used, both of which were prepared in a xylene solvent by homogenously mixing a silicate resin, xylene, and a silicone fluid. The mixture was then heated, stripped of non-volatile content, and eventually redissolved in hexane to a non-volatile content of 50 wt %. The final 17-beta estradiol-containing adhesive solution was cast onto a polyester release liner, allowed to air dry, and then laminated onto a polyester backing film.
WO 00/33812 describes a transdermal patch for administering a volatile liquid drug, such as nicotine. The transdermal patch contains a backing layer, a pressure sensitive silicone adhesive layer and a pressure sensitive acrylic adhesive layer containing the drug, and a removable release liner layer. The silicone adhesive layer is prepared by dissolving a silicone adhesive in hexane. WO 00/33812 reports (at p. 6) that other solvents, such as heptane and toluene, are not suitable because they require higher processing temperatures and thus result in more drug degradation and/or evaporation during coating and drying.
WO 96/40085 describes transdermal matrix patches for administering drugs, such as selegiline, nitroglycerin and nicotine, which are liquid at normal room temperature. WO 96/40085 suggests making a monolithic matrix of the drug in an adhesive by mixing one or more polymeric adhesives, preferably polyacrylate and polysiloxane, and the drug in a volatile solvent, casting the mixture, and evaporating the solvent. Examples of volatile solvents provided are isopropanol, ethanol, xylene, toluene, hexane, cyclohexane, heptane, ethyl acetate and butyl acetate.
Similarly, U.S. Pat. No. 5,603,947 describes in Example 1 the use of heptane to cast a silicone adhesive layer in nicotine patches.
In both of the above references, the drugs are dissolved in the silicone adhesives prior to casting.
Transdermal patches containing fentanyl in a silicone pressure sensitive adhesive are also known in the art, as described, for example, in U.S. Pat. Nos. 4,588,580 (Gale et al.) and 5,186,939 (Cleary et al.), also fully incorporated herein by reference.
U.S. Pat. No. 4,588,580 describes in Example 6 a fentanyl-containing monolithic patch that was made using Dow Corning amine resistant silicone adhesive and silicone medical fluid having 10 and 20 percent fentanyl base dispersed therein.
U.S. Pat. No. 5,186,939 describes a laminated composite for administering fentanyl transdermally, including an adhesive-drug reservoir layer comprising fentanyl dissolved in an amine-resistant polydimethylsiloxane. Example 1 describes that a fentanyl-containing pressure sensitive adhesive composition was prepared consisting of 1.8% fentanyl base, 4% permeation enhancer (PGML), 2.0% silicone oil (Dow Corning Medical Fluid) and 92.5% amine resistant polydimethylsiloxane (Dow Corning X7-2900) dissolved in trichlorotrifluoroethane (freon) to provide a 50% solution.
In addition, a fentanyl-containing, reservoir-type transdermal patch as approved by the FDA is described in the 2002 Physician's Desk Reference. Duragesic® is a rectangular transparent patch comprising a protective liner and four functional layers. Proceeding from the outer surface toward the surface adhering to the skin, these layers are: 1) a backing layer of polyester film; 2) a drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetate copolymer membrane that controls the rate of fentanyl delivery to the skin surface; and 4) a fentanyl containing silicone adhesive.
The present invention is believed to offer improvements and advantages over prior fentanyl-containing transdermal devices.